EP1206458A1 - Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments - Google Patents

Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments

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Publication number
EP1206458A1
EP1206458A1 EP00962367A EP00962367A EP1206458A1 EP 1206458 A1 EP1206458 A1 EP 1206458A1 EP 00962367 A EP00962367 A EP 00962367A EP 00962367 A EP00962367 A EP 00962367A EP 1206458 A1 EP1206458 A1 EP 1206458A1
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EP
European Patent Office
Prior art keywords
alkyl
substituted
methyl
halogen
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00962367A
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German (de)
English (en)
Inventor
Peter Hölscher
Hartmut Rehwinkel
Stefan Jaroch
Detlev Sülzle
Margrit Hillmann
Gerardine Anne Burton
Fiona Mcdougall Mcdonald
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1206458A1 publication Critical patent/EP1206458A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the invention relates to benzoxazine and benzothiazine derivatives, the process for their preparation and their use in medicaments.
  • NOS nitric oxide synthases
  • ncNOS or NOS 1 constitutive NO synthases
  • ecNOS or NOS 3 endothelium
  • iNOS ode r NOS 2 is a virtually Ca ++ independent enzyme and is induced by endotoxin or other substances, after activation of different cells.
  • NOS inhibitors and in particular selective inhibitors of NOS 1, NOS 2 or NOS 3 are therefore suitable for the therapy of various diseases which are caused or exacerbated by pathological concentrations of NO in cells.
  • a number of reviews provide information on the effects and inhibitors of NO synthases. Examples include: Drugs 1998, ⁇ , 321 or Current Pharmac. Design 1997, 3, 447.
  • NOS inhibitors Different compounds are known as NOS inhibitors. For example, arginine derivatives, aminopyridines, cydic amidine derivatives, phenylimidazoles and others are described. From WO 98/50372 it is known that 3-amino-2H-1, 4-benzoxazines or -benzothiazines potent and selectively inhibit nitric oxide synthases.
  • the invention relates to the compounds of formula I, their tautomeric and isomeric forms and salts
  • R is hydrogen or
  • R 4 is hydrogen or acyl
  • R 5 and R 6 are independently hydrogen, C 3 . 7- cycloalkyl, phenyl, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl radicals, which can each be substituted with halogen, OH, 0-de-alkyl, SH, SC 1-6 Alkyl, NR 15 R 16 , 5- or 6-membered hereroaryl with 1 - 3 N, O or S atoms, phenyl or C 3-7 cycloalkyl,
  • R 7 is hydrogen, d- 6 alkyl, which may be substituted with phenyl, COOC ⁇ -6 alkyl or COC ⁇ . 6 alkyl,
  • R 8 is hydrogen
  • D is hydrogen or - (CH 2 ) P -U
  • U is hydrogen, optionally substituted with halogen -6- alkyl, C 3-7 cycloalkyl, indanyl, C 7-1 o-bicycloalkyl, C ⁇ -io-aryl or 5- or ⁇ giiederiges heteroaryl with 1-3 N-, O- or S atoms, which can be fused with benzene, where the aryl and heteroaryl radicals can be substituted with halogen, C 1-4 alkyl, C 1- alkoxy, CF 3 , NO 2 , NH 2 , N (C 1-4 alkyl) ) 2 , cyano, CONH 2 , -O-CH 2 -O-, -O- (CH 2 ) 2 -O-, SO 2 NH 2 , OH, phenoxy or COOC ⁇ alkyl,
  • R 8 and B together with the nitrogen atom form a 5-7-membered saturated heterocycle which contains a carbonyl or thiocarbonyl group and may optionally contain a further oxygen, nitrogen or sulfur atom and with or a phenyl, benzyl or benzoyl radical which may be substituted by halogen or may be substituted
  • R 7 and A together with the nitrogen atom form a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom or form an unsaturated ⁇ -membered heterocycle which can contain 1-3 N atoms,
  • R and R are hydrogen or C ⁇ _g-alkyl
  • R 11 C- ⁇ e-alkyl, -NH2, -NH-CH3, -NH-CN, optionally substituted with halogen, C ⁇ _4-alkyl or CF3 Cg-ioryl or optionally substituted with halogen, C-j_4-alkyl or CF3 5 - or ⁇ -membered heteroaryl with 1 to 4 nitrogen, sulfur or oxygen atoms,
  • R and R are hydrogen, C-
  • R is hydrogen, hydroxy, -6 alkoxy, phenyl, optionally with CÜ2H, CO2C1.6- alkyl, hydroxy, C-
  • R 15 and R 16 are hydrogen, C ⁇ . 6 alkyl, optionally with halogen or substituted phenyl or optionally substituted with halogen or d- alkyl
  • Benzyl or R 15 , R 16 together with the nitrogen atom form a saturated 5-, 6- or 7-membered ring which can contain a further nitrogen, oxygen or sulfur atom and can be substituted by C -] _ 4-alkyl or an optionally substituted by halogen Phenyl, benzyl or Be ⁇ zoylrest
  • the compounds of formula I can exist as tautomers, stereoisomers or geometric isomers.
  • the invention also encompasses all possible isomers, such as E and Z isomers, S and R enantiomers, diastereomers, racemates and mixtures thereof, including the tautomeric compounds of the formulas Ia and Ib
  • the physiologically acceptable salts can be formed with inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.
  • inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.
  • the inorganic or organic bases which are known for the formation of physiologically compatible salts, such as, for example, alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Tris, are also suitable for salt formation of acid groups - (hydroxymethyl) methylamine etc.
  • physiologically compatible salts such as, for example, alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Tris, are also suitable for salt formation of acid groups - (hydroxymethyl) methylamine etc.
  • Alkyl means in each case a straight-chain or branched alkyl group such as e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, neopentyl, n-hexyl., Sec. Hexyl, heptyl, octyl.
  • alkyl means in each case a straight-chain or branched alkyl group such as e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, neopentyl, n-hexyl., Sec. Hexyl, heptyl
  • alkyl radical U is substituted by halogen, it can be halogenated one to more times, in particular perhalogenated such as CF 3 , C 2 F 5 , CH 2 F, 2-fluoroethyl.
  • Alkenyl and alkynyl substituents are each straight or branched.
  • the following radicals may be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl , 2-butynyl, 2-pentenyl, 4-hexenyl.
  • Cycloalkyl is understood to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Bicycloheptane and bicyclooctane are examples of bicycles.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Aryl is to be understood in each case as naphthyl or phenyl, which can be substituted one to three times in the same or different ways.
  • heteroaryl radicals which can be bonded via the hetero atom or a carbon atom:
  • 2-C 1 is also a heteroaryl radical. 6- alkyl-3-amino-2H-1, 4-benzoxazine and 2-d -6- alkyl-3-keto-2H-1, 4-benzoxazine are suitable.
  • heteroaryl radical If the heteroaryl radical is substituted, it can be substituted one to three times in the same or different manner.
  • Thienyl is to be considered as a preferred embodiment for R in the meaning heteroaryl.
  • Saturated heterocycles are to be understood in each case, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine and piperazine.
  • the heterocycle can be substituted 1-3 times, identically or differently, with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen. Examples include: N-methylpiperazine, 2,6-dimethylmorpholine, pyrrolidine, phenylpiperazine or 4- (4-fluorobenzoyl) piperidine. If -NR 7 A- forms an unsaturated heterocycle together with the nitrogen atom, for example imidazole, pyrrole, pyrazole and triazole may be mentioned.
  • the substituent Q can be linked at any point via a carbon atom or, if appropriate, via an nitrogen atom.
  • R and R form a ring together with two adjacent carbon atoms, this ring can be in position 5, 6 or 7, 8 or in particular 6, 7 of the benzoxazine or benzothiazine and has the formula
  • the substituent r is in particular zero.
  • two adjacent carbon atoms of the aromatic are linked with C 3-6 alkylene, in particular Cs ⁇ alkylene, to form a 5-8-membered ring E, in particular to form a 5-6-membered ring.
  • the acyl radical R is derived from straight-chain or branched aliphatic C 1-6 carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid or from known benzenesulfonic acids, which can be substituted by halogen or C 1-4 alkyl, and C-
  • _4-alkanesulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid.
  • the substituent n is preferably 1-6, in particular 1.
  • Preferred embodiments for X are S and in particular O.
  • R 3 , R 4 , R 7 and R 9 are each hydrogen.
  • the substituent R 1 is preferably in the 6-position.
  • the ring E is preferably monosubstituted, the substituent being in the 6-position.
  • a preferred embodiment of A is straight or branched If R 8 and B form a saturated heterocycle together with the nitrogen atom, pyrrolidin-2-thione is particularly meant.
  • Preferred embodiments for D are hydrogen and - (CH 2 ) P -U in the meaning of optionally with halogen, -C 4 alkoxy, CF 3 or substituted benzyl radical.
  • P and q preferably do not mean 0 at the same time, but either p or q is an alkylene radical having 1-6 carbon atoms.
  • the invention also relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment of diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations.
  • diseases which are caused by the action of
  • Examples include:
  • Cerebral ischemia hypoxia and other neurodegenerative diseases that are associated with inflammation such as multiple sclerosis, amyotrophic lateral sclerosis and comparable skierotic diseases, Parkinson's disease, Huntington's disease, Korksakoff's disease, epilepsy, vomiting, sleep disorders, schizophrenia, depression, stress, pain, Migraines, hypoglycemia, dementia such as Alzheimer's disease, HIV dementia and presenile dementia.
  • the compounds according to the invention are very suitable for inhibiting the neuronal NOS.
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active substance for enteral or parenteral administration, contains suitable carriers, auxiliaries and / or additives.
  • the application can be administered orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can optionally be used subcutaneously or topically or intramuscularly take place intrathecally.
  • the inert organic and inorganic carrier materials known to the person skilled in the art are suitable as auxiliaries for the desired pharmaceutical formulation, e.g. Water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. If necessary, you can also use
  • Preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers may be included.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 1 - 2000 mg, preferably 20 - 500 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.
  • NOS inhibitory activity of the compounds of the formula I and their physiologically tolerable salts can be determined by the methods of Bredt and Snyder in Proc. Natl. Acad. Be. USA (1989) 86, 9030-9033.
  • the compounds of the invention are prepared by adding a compound of the formula II or its salt
  • R 1 , R 2 , R 3 , R 5 , R 6 and X have the above meaning, Z is oxygen or sulfur and R C-
  • _5-alkyl means reacted with ammonia or primary amines, amino groups present being optionally protected as intermediates, and if desired subsequently acylated, the isomers separated or the salts formed.
  • reaction with ammonia is possible under pressure in autoclaves with excess ammonia at low temperatures (-78 ° C.) or by stirring in methanol saturated with ammonia at room temperature.
  • Thiolactams are preferably reacted.
  • the imine ether or iminothioether is first prepared from the lactam or thiolactam as an intermediate compound (e.g. with methyl iodide or methyl sulfate) and is reacted with or without isolation of the intermediate compound with the corresponding amines or their salts.
  • amino protecting groups are carbamates such as tert. Butoxy-carbonyl, Benzyloxycarbonyi or acetyl suitable.
  • sulfides are oxidized on the precursors, saponified esters, esters esterified, hydroxyl groups etherified or acylated, amines acylated, alkylated, diazotized, halogenated, NO2 introduced or reduced, reacted with isocyanates or isothiocyanates, the isomers separated or the salts formed.
  • the saponification of an ester group can be carried out basic or acidic by at room temperature or elevated temperature up to the boiling point of the reaction mixture in the presence of alkali metal hydroxides in ethanol or other alcohols or by means of acids such as e.g. Hydrolysed hydrochloric acid and optionally further processed salts of the aminobenzoxazines or thiazines.
  • the carboxylic acid is esterified in a manner known per se
  • Diazomethane or the corresponding alcohol in acid or in the presence of an activated acid derivative examples include acid chloride, imidazolide or anhydride.
  • suitable acid derivatives are acid chloride, imidazolide or anhydride.
  • the reduction of an ester group to alcohol is carried out in a manner known per se using DiBAH in a suitable solvent at low temperatures.
  • the reductive amination of a ketone or a benzaldehyde with amine with the addition of a borohydride gives benzylic amines. With appropriately chosen diamines, symmetrical or asymmetrical amino compounds are obtained after addition of the same or different aldehydes or ketones.
  • a nitro group or halogen, especially bromine can be introduced by electrophilic aromatic substitution.
  • the resulting mixtures can be separated in the usual way, also by means of HPLC. If a nitrile is present, it can be saponified by known processes or converted into the corresponding amine, tetrazole or amidoxime or it becomes a substituted amidine by attacking substituted anilines or amines.
  • Friedel-Crafts acylation is successfully used for type Ila lactams, and then the lactam can be selectively converted to the thiolactam or the acylation product reductively aminated.
  • Suitable catalysts are metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally in the presence of barium sulfate or on supports.
  • metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally in the presence of barium sulfate or on supports.
  • ammonium formate or formic acid can also be used in a known manner.
  • Reducing agents such as tin-II-chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts. It may be advantageous to introduce the ester group as in formula V before the reduction.
  • the reduction with zinc or iron in acetic acid has proven effective for nitro groups.
  • alkylation can be carried out using alkyl halides, for example, using conventional methods. If necessary, protection of the lactam group as an anion by a second equivalent base or by a suitable protective group is required.
  • the amino group is acylated in a customary manner, for example using an acid halide or acid anhydride, if appropriate in the presence of a base.
  • the introduction of the halogens chlorine, bromine or iodine via the amino group can also take place, for example, according to Sandmeyer by reacting the diazonium salts formed intermediately with nitrites with Cu (l) chloride or Cu (l) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid implemented with kaiium iodide.
  • benzyl alcohols can be converted into the corresponding benzyl halides using methanesulfonyl chloride.
  • N ⁇ 2 group succeeds through a number of known nitration methods.
  • nitrates or nitronium tetrafluoroborate can be nitrated in inert solvents such as halogenated hydrocarbons or in sulfolane or glacial acetic acid. It is also possible to introduce e.g. by nitrating acid in water or conc. Sulfuric acid as a solvent at temperatures between -10 ° C and 30 ° C.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
  • the enantiomers or enantiomerically pure diastereomers can also be obtained by chromatography on chiral phases and by stereoselective synthesis.
  • the salts are prepared in a customary manner by adding a solution of the compound of the formula I - optionally also with protected amino groups - with the equivalent amount or an excess of an acid, which is optionally in solution, and separating off the precipitate or in a conventional manner worked up the solution.
  • benzylamines provide nucleophilic substitution of benzyl halides with secondary amines.
  • Meerwein reagent trimethyloxonium tetrafluoroborate
  • the compounds of the formula IIIa can be prepared, for example, by adding a compound of the formula III
  • R ⁇ and R ⁇ have the above meaning and Y is a reactive carboxyl group such as acid halide, nitrile, carboxylic acid ester and optionally reductively cyclized or by reacting a compound of formula V.
  • Aromatic thiols of type III are obtained, among other things, as described in Chem. Pharm. Bull. 1991, 39, 2888 and the literature mentioned there, by rearrangement of the corresponding dimethylaminothiocarbamates.
  • the substituents R 1 to R 3 can be introduced at the stage of the compounds of the formula III or II.
  • the aldehyde or the ketone of the corresponding 1,4-benzoxazin-3-one or 1,4-benzothiazin-3 (4H) -one can be reductively aminated. This is also possible twice with diamonds chosen appropriately.
  • Diamines can also be reacted with the aldehyde of 1,4-benzoxazin-3-one and, at the same time, with other aldehydes chosen appropriately.
  • the introduction of a heteroaryl radical Q is desired, the corresponding haiogen derivative can be nucleophilically substituted with amine.
  • a primary or secondary amino group it may be advantageous to protect it intermediately, for example by introducing a tert-butoxycarbonyl group which is split off in a conventional manner after the amidine formation.
  • monoacylated diamines can also be obtained by reacting benzamides with diamine with the release of ammonia.
  • New compounds were characterized by one or more of the following methods: melting point, mass spectroscopy, NMR.
  • NMR spectra were measured with a Bruker 300 MHz device, the (deuterated) solvents are abbreviated as follows: CDCI3 (chloroform), DMSO (dimethyl sulfoxide). Shifts are given in delta and ppm. They mean: m (multiplet, multiple signals), s (singlet), d (doublet), dd (double doublet, etc.), tr (triplet), q (quartet), H (hydrogen protons), J (coupling constant).
  • Trifluoroacetamide and 1,4-butanediamine are used as in the literature (Synthesis 11; 1988;
  • 6-formyl-2-methyl-2H-1,4-benzoxazin-3 (4H) -one is described in DE-198 26 232.9, as is that of 6-formyl-2-ethyl-2H-1,4 -benzoxazin- 3 (4H) -one and 6-formyl-2-propyl-2H-1, 4-benzoxazin-3 (4H) -one.
  • the product also contains N r2-methyl-2H-1.4-benzoxazin-3 (4H) -onl-6-yl -methyl-
  • 6-frN- (4-chlorobenzyl) pentanecarboxamide-6-v ⁇ - (tert-butyloxycarbonyl) aminomethyl) -2-methyl-2H-1.4-benzoxazin-3 (4H) -one 129 mg 6 - ⁇ [N- (4-chlorobenzyl) pentanecarboxamide-6-yl] aminomethyl ⁇ -2-methyl-2H-1,4-benzoxazin-3 (4H) -one in 8 ml dichloromethane with the addition of 0.127 ml triethylamine and 163 mg di-tert Stir in butyl dicarbonate.
  • Nr (3-amino-2-methyl-2H-1.4-benzoxazin-6-v ⁇ -methyl- (tert.-butyloxycarbonyl) aminol-n-butvI-N'-phenvIurstoff 6- (rN- (pyrrolidin-2-thione ) -prop-3-yll- (tert-butyloxycarbonyl) aminomethyl> -3-amino-2-methyl-2H-1.4-benzoxazine

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Abstract

L'invention concerne des composés de formule (I), leurs formes tautomères et isomères et leurs sels, un procédé pour leur préparation ainsi que leur utilisation dans des médicaments.
EP00962367A 1999-08-25 2000-08-23 Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments Withdrawn EP1206458A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19941115 1999-08-25
DE19941115A DE19941115A1 (de) 1999-08-25 1999-08-25 Neue Benzoxazin- und Bezothiazin-Derivate und deren Verwendung in Arzneimitteln
PCT/EP2000/008240 WO2001014347A1 (fr) 1999-08-25 2000-08-23 Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments

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EP1206458A1 true EP1206458A1 (fr) 2002-05-22

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US (2) US7141566B1 (fr)
EP (1) EP1206458A1 (fr)
JP (1) JP2003507460A (fr)
AU (1) AU7412500A (fr)
DE (1) DE19941115A1 (fr)
NO (1) NO20020883L (fr)
WO (1) WO2001014347A1 (fr)

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DE10020667A1 (de) * 2000-04-19 2001-11-22 Schering Ag Neue Benzoxazin- und Benzothiazin-Derivate und deren Verwendung in Arzneimitteln

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EP0980362B1 (fr) * 1997-05-02 2006-08-16 Schering Aktiengesellschaft Heterocycliques substitues et leur utilisation dans des medicaments
KR20010023746A (ko) * 1997-09-08 2001-03-26 에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만 벤족사진 및 벤조티아진 유도체 및 그의 제약 제제로서의용도
WO1999023092A2 (fr) 1997-10-31 1999-05-14 Neurogen Corporation 3-aminoalkylamino- 2h-1,4-benzoxazines et 3-aminoalkylamino- 2h-1,4-benzothiazines constituant des ligands specifiques d'un sous-type de recepteur de la dopamine

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WO2001014347A1 (fr) 2001-03-01
AU7412500A (en) 2001-03-19
US20070049583A1 (en) 2007-03-01
NO20020883D0 (no) 2002-02-22
JP2003507460A (ja) 2003-02-25
DE19941115A1 (de) 2001-03-01
NO20020883L (no) 2002-04-05
US7141566B1 (en) 2006-11-28

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